Psycho-Babble Medication Thread 591969

In reply to Re: What to do if Nardil and Parnate were discontinued, posted by Tomatheus on December 27, 2005, at 21:02:56

Dear Tom

>Sorry, I didn't mean to be hurtful, but I don't think that there's enough evidence to suggest that a "vast majority" of Nardil responders will be able to find another medication or med combo that provides clinically significant relief from the symptoms of their psychiatric illnesses.

In reply to Re: What to do if Nardil and Parnate were discontinued » Tomatheus, posted by linkadge on December 28, 2005, at 11:03:31

Hi Link

AFAIK........In the absense of MAO-A, serotonin is metabolised by MAO-B. As shown in the study I posted above, clorgyline only mildly increased serotonin levels wheareas Nardil greatly increased serotonin levels. This could be an important reason why moclobemide's efficacy may be less than that of Nardil.

In reply to Re: What to do if Nardil and Parnate were discontinued, posted by Tomatheus on December 27, 2005, at 21:02:56

Hi Tom

Pirlindole has been researched mainly in Russia. Pirlindole is not a new drug by any means. Numerous psychiatric drugs invented in Russia, France, Japan, Hungary etc have only been marketed in their 'home country'.

In reply to Re: What to do if Nardil and Parnate were discontinued » Tomatheus, posted by linkadge on December 28, 2005, at 11:03:31

Linkadge,

See below for my responses...

> Its funny. They probably don't see new MAOI's as advances over Nardil/Parnate, but yet they're willing to release SSRI after SSRI.

Yeah, in terms of introducing medications that might actually produce clinically significant benefits in treatment-resistant patients, it really doesn't make sense why more MAOIs haven't been pursued. However, you know as well as I know (or probably better) that the drug companies are more interested in making meds that will maximize their profits than those that could potentially help a relatively small group of treatment-resistant patients. I'm not saying at all that these small groups of patients are insignificant, but the drug companies obviously don't stand to make as much money off of meds that that are targeted toward a subgroup of depressed patients as they do from so-called "blockbuster" meds that they can market to all patients with depressive disorders, patients with other psychiatric conditions, and patients who just feel "down" for a short period of time as a result of circumstances in the lives. And of course, if the drug companies can claim that a particular class of drugs is safe -- and if they have the power to discredit anyone who dares to suggest otherwise -- they can succeed at at getting people with a wide range of depressive symptoms (including those that can be directly attributed to "depressing" life circumstances) to request these drugs from their doctors. Because the capacity of the irreversible MAOIs (including the selective MAO-A inhibitors clorgyline and Lilly 51641) to potentiate hypertensive crises has been well-known for decades, it would be impossible for the drug companies to market them as "safe." This of course would translate into a low profit potential from such medications.

I should also probably clarify that Lilly 51641 is actually not a "new" MAOI, but a medication that Lilly began pursuing in the mid-1960s. Lilly 51641 was studied experimentally until the late 1970s, but I have not been able to find any information to indicate to what extent (and for how long) Lilly was actually trying to pursue the drug for commercial use. But considering that Lilly is a commercial drug company, it would make sense that they were trying to pursue it at one point. It seems likely that that Lilly decided against pursuing it as a commercial drug because of its ability (like that of clorgyline) to potentiate hypertensive crises. According to Lotufo-Neto et al. (1999), "Clorgyline is an irreversible enzyme inhibitor, and has some liability to cause hypertensive crises in the face of high substrate concentrations, despite its selectivity (Laux et al., 1995, as cited in Lotufo-Neto et al.). Thus, clorgyline was not considered to represent much of an advance over the nonselective MAOIs and was not vigorously pursued."

> Where I do think that mixed MAO-A/B inhibitors have the advantage over MAO-A inhibitors is in the subset of people who gain a significant antidepressnat effect from increased PEA neurotransmission. > > Some doctors have detected low PEA neurotransmission in certain subsets of depression. Depression that is accompanied by low energy, cravings, poor attention and other features.

I think you could be right.

I also think that there is a subgroup of individuals who stands to benefit from the selective inhibition of MAO-A. Studies that have measured MAO-A levels in cultured skin fibroblasts and placentas have found that levels of the enzyme vary "over 50-fold" among control individuals (Hotamisligil & Breakfield, 1991). Furthermore, variants of the MAO-A gene that encode for abnormally high levels of the enzyme have shown statistically significant associations with major depression and sleep disturbance in males (Du et al., 2004); depressed suicide in males (Du et al, 2002); major depression in females (Schulze et al., 2000); panic disorder in females (Deckert et al, 1999); anxiety disorders, agoraphobia, and specific phobias in females (Samochowiec et al., 2004), and ADHD in children (Domschke et al., 2005; Jiang et al., 2001). In my opinion, it seems possible that in some individuals, the genetic tendency to produce abnormally high levels of MAO-A could be just one of multiple genetic abnormalities that contributes to their illness. And the relationship between the abnormally high MAO-A levels and the ways in which the associated psychiatric illnesses manifest themselves does seem to be different in males than it is in females. This could be because the MAO-A gene is located on the X chromosome, because of estrogen's ability to influence MAO-A activity MAO-A activity (Chakravorty et al., 1997), or possibly both. But it seems clear that there are some individuals whose psychiatric symptoms are at least partially mediated by genetically determined high levels of MAO-A. Furthermore, MAO-A activity has been reported to rise significantly with aging (Hotamisligil et al., 1991), indicating that the selective inhibition of MAO-A may be beneficial in treating geriatric depression. So, between the genetic tendencies to produce abnormally high levels of MAO-A and the potential that hormonal differences could also influence MAO-A levels, there is little doubt in my mind that there are some individuals (note: I'm not saying *all* individuals) who would benefit from a potent selective inhibitor of MAO-A.

> These people are not going to get major help from SSRI, SNRI's, and probably never will.

In reply to Re: What to do if Nardil and Parnate were discontinued » Tomatheus, posted by ed_uk on December 28, 2005, at 13:54:06

> >What I wanted to say was that moclobemide is the only commercially available medication available anywhere in the world that is highly preferential to MAO-A over MAO-B. > > Like moclobemide, pirlindole is considered to be a RIMA.

Ed,

Thanks for the clarification. Like I said in the last post I wrote to you, I was not aware of pirlindole from the research studies that I had read, and I thank you for making me aware of the presence of pirlindole. I was just trying to restate what I was meaning to write in my *first* post because my statement in that first post accidentally ended up being erroneously wrong (I think I said that moclobemide was the only commercially available *MAOI* available anywhere in the world).

In reply to Re: What to do if Nardil and Parnate were discontinued » linkadge, posted by Tomatheus on December 28, 2005, at 14:38:54

Hi T

Thanks for the interesting post :)

>there is little doubt in my mind that there are some individuals (note: I'm not saying *all* individuals) who would benefit from a potent selective inhibitor of MAO-A

I agree, very much so.

I've often wondered whether p-babble has created an unrealistically negative impression of moclobemide. Most babblers who've taken moclobemide have been very treatment resistant (they have generally imported it into the US following multiple unsuccesful trials of other ADs). Moclobemide has, after all, proved to be an effective antidepressant in numerous clinical trials.

Moclobemide's official maximum dose is 600mg/day (300mg bid). Nevertheless, some sources have suggested that doses up to 1200mg/day might be necessary. Given moclobemide's reversibility and short duration of action, some patients might benefit from taking it in multiple divided doses eg. 150-300mg four times a day. Having said that, I'm sure other people can benefit from much less!

In reply to Moclobemide vs P-babble » Tomatheus, posted by ed_uk on December 28, 2005, at 15:23:07

Ed,

I think you made some valid points concerning moclobemide. As you mentioned, moclobemide has demonstrated clinical efficacy in several clinical trials. In a meta-analysis of moclobemide and brofaromine, Lotufo-Neto et al. (1999) found that moclobemide tends to be significantly more effective than placebo, about as effective as the SSRIs, and slightly less effective than the irreversible MAOIs.

And I agree that the Babblers who have taken moclobemide for depression are most likely not representative of the depressed population as a whole. Many of us here are relatively treatment resistant, so if we're more likely to be unresponsive to most drugs than most depressed patients, the same likely holds true for moclobemide. I will say that I've read that moclobemide tends to be less effective in practice than the research studies suggest. Unfortunately, I can't seem to find the source that suggested that right now, so I can't say for sure how valid that point was. I also recall reading that moclobemide was once used as a first-line treatment in New Zealand but has since dropped to second or third-line use because of its lack of efficacy. So, I think the evidence concerning moclobemide's efficacy is mixed, but I still think that the most valid sources would have to be the clinical trials, which (as you mentioned), have shown moclobemide to be relatively effective.

I also recall reading in a research study (but I can't remember which one) that some patients might benefit from doses higher than 600mg/day. And I definitely agree that the moclobemide dosing schedule likely to produce the most benefits would be the one you suggested -- dividing the dose so its taken several times a day at regular intervals. I personally tried that strategy without any success, but just because I didn't respond to moclobemide obviously doesn't mean that others won't. As I've hypothesized in other posts (see http://www.dr-bob.org/babble/20051221/msgs/591806.html if you're interested), I think that an MAOI's ability to inhibit the MAO enzymes consistently has a lot to do with the drug's efficacy. Or it's at least one important factor, IMHO. So, for some patients, it does make sense that taking moclobemide several times a day at regular intervals might be enough to do the trick.

In reply to Re: What to do if Nardil and Parnate were discontinued » linkadge, posted by Tomatheus on December 28, 2005, at 14:38:54

The really dumb thing, is that if the drug companies want to target as many people as possable, they might almost want to try the MAO inhibitor route.

SSRI's don't routeenly or consistantly make the average person better than well. MAO's on the other hand, were discovered based on their propenisty to make normal people feel better than well.

MAO's could also be targeted towards the cigarette smokers. Parnate could probably get more people off the cigarettes than could say wellbutrin, since smoking is not purely dopaminergic. Tobacco inhibits both MAO A, and B.

I know that the drug companies have marketed the SSRI's for everything upto and including a bad hair day, mainly because they can. I don't think they have that option with MAOIs. Also a lot of people's depression is not so bad that they would have to give up on sausage.

If MAOI's were not as "dangerous", the drug companies could probably do the same with the MAOI's that they did with the SSRI's.

I would argue that the only reason the SSRI's are so widely distributed is reated to their presumed safety. I think that even the notion that MAOI's "only help a small subset of depressed people", is just a drug company attempt to direct us towards the newer SSRI drugs. How do we know that they only help a small subset of the depressed population? They've only been given to a small subset of depressed people. Maybe if they were used first line, remission rates would be higher.

For all the placebo's I have ingested over the years, parnate was really the only "active drug".I won't likely get another shot at an MAOI. No doctor wants to take the "risk"

In reply to Re: Moclobemide vs P-babble » ed_uk, posted by zeugma on December 28, 2005, at 16:26:16

I agree that the preception of a drug can dramatically affect its use. How many people are on a particular drug these days because their doctor told them it worked better?

There are a lot of unsubstantiated opinions out there that frame the way doctors approach drugs.

How do you get people on drugs? The more people who simply try the drug, the more people who will continue taking it. As long as a drug is better than nothing, and widely distributed, it could become sucessfull.

I think that moclobemide is probably not prescribed that much, because it just seems like the "odd one out", with all of the SSRI's about.

In reply to Re: What to do if Nardil and Parnate were discontinued, posted by linkadge on December 28, 2005, at 18:33:24

Linkadge,

My responses are below...

> MAO's could also be targeted towards the cigarette smokers. Parnate could probably get more people off the cigarettes than could say wellbutrin, since smoking is not purely dopaminergic. Tobacco inhibits both MAO A, and B.

That might not be such a bad idea. The only problem I see with it is that some smokers might not be willing to give up the forbidden tyramine-containing foods if they're not willing to give up smoking.

> If MAOI's were not as "dangerous", the drug companies could probably do the same with the MAOI's that they did with the SSRI's.

I think you're absolutely right.

> I would argue that the only reason the SSRI's are so widely distributed is reated to their presumed safety. I think that even the notion that MAOI's "only help a small subset of depressed people", is just a drug company attempt to direct us towards the newer SSRI drugs. How do we know that they only help a small subset of the depressed population? They've only been given to a small subset of depressed people. Maybe if they were used first line, remission rates would be higher.

It looks like I wrote my statement regarding the drug companies' lack of interest in helping a small subset of depressed people without thinking of the context I was putting it in. I do think that the drug companies are more interested in making drugs that they can market to large numbers of people than they are in making drugs that would likely only be prescribed to a relatively small number of depressed individuals. And I think you're absolutely correct in stating that MAOIs would help more people if more doctors were to prescribe them.

With respect to the idea that MAOIs only help a small subset of depressed patients, I would actually argue (or perhaps I should say "speculate") that most, if not all, antidepressants only help relatively small percentages of patients -- at least when factors such as the placebo effect and the lack of long-term studies are taken into account. As critics of psychiatry often argue, it's difficult to determine whether or not any given antidepressant actually "helps" depressed patients based on clinical trials that only last four to six weeks. I know that I'm just speculating here, but my guess is that all antidepressants would actually turn out to be effective in less than 50 percent of those with endogenous depressive disorders if an "effective" drug were to be defined as one that produces a clinically significant response in a patient over an extended period of time.

So, I'm not really trying to say that the MAOIs only help a small number of depressives in comparison to the SSRIs. I haven't personaly come across any reserch studies that have directly compared an MAOI with an SSRI, but I would be surprised if such a study hasn't been done. Based on the limited amount of research material that I've read, it seems that the MAOIs would be at least comparable to the SSRIs in terms of their efficacy. After all, judging from meta-analysis data that moclobemide tends to be about equally as effective as the SSRIs but less effective than the irreversible MAOIs (Lotufo-Neto et al., 1999), it would seem that MAOIs might actually be more effective than the SSRIs. So, even though I think that the notion of the MAOIs only being effective in a small subset of depressed patients is somewhat problematic (mostly because a "small subset" can mean a minority as small as 1 percent or something more like 30 percent), I think the bigger problem is the tendency of the drug companies to create the impression that SSRIs are highly effective.

> For all the placebo's I have ingested over the years, parnate was really the only "active drug".> I won't likely get another shot at an MAOI. No doctor wants to take the "risk"

In reply to Re: What to do if Nardil and Parnate were discontinued » linkadge, posted by Tomatheus on December 28, 2005, at 21:14:16

No I know what you are saying.

Not so much based on what you said.

I remember reading about the definition of an MAO inhibitor on a SSRI website (can't recall which one). Basically it tried to give the idea that they were old fashoned drugs, and that the newer SSRI's were safer and more effective.

In reply to Re: What to do if Nardil and Parnate were discontinued » linkadge, posted by ed_uk on December 29, 2005, at 16:52:21

Indeed! I never understood how someone who got to the point where they wished to take medication for psychological reasons would be aversive to following a diet that's easier than the diabetic diet, for example. Hmm, being unable to walk from my desk to the cafeteria at work without feeling waves of terror as all of the people are "staring" at me and running back to my desk after I get my food...or don't eat high tyramine foods? Lay about my apartment, depressed, lethargic, paralyzed with doubt, my mind spinning endless web of thoughts about what could go wrong with every choice or move I make or could make, or give up fine, air-dried sausage? Not be able to sustain enough attention to read through a book I earnestly want to read and find interesting because I have to keep rereading every paragraph five or more times just to feel as if I'm "getting it", or forego soy sauce on my sushi?

HAAAHAHAHAHAHAHAHHAAHHAHAHAHHAHHAHAHA, MAN, THE LAUGHING HURTS!

And let us not forget that 10mg of nifedipine, phentolamine, or 0.1-0.3mg clonidine will rapidly ameliorate the hypertensive crisis.

In reply to Re: What to do if Nardil and Parnate were discontinued » ed_uk, posted by Chairman_MAO on January 2, 2006, at 12:12:11

Hi Chair

I'm not sure why you posted that to me :-SYou sound angry.

Anyway......

>don't eat high tyramine foods?

The problem is, many people who suffer from anxiety are likely to be frightened of having a hypertensive crisis. I don't think this is unrealistic. 'Brain selective' MAOIs could offer an important medical advance.

In reply to Re: What to do if Nardil and Parnate were discontinued » Chairman_MAO, posted by ed_uk on January 2, 2006, at 12:47:50

Hopefully phenelzine will be continued for all responders. During my trial I took the concord one (uk), unfortunately an import because here is only the moclobemide sold which does not work for most but makes more money for Roche pharmaceuticals.Happy new year anyway!

In reply to Re: What to do if Nardil and Parnate were discontinued » Chairman_MAO, posted by ed_uk on January 2, 2006, at 12:47:50

Hi Ed,

The problem is, many people who suffer from anxiety are likely to be frightened of having a hypertensive crisis. I don't think this is unrealistic. 'Brain selective' MAOIs could offer an important medical advance.>>

As an anxious person (especially about food, becoming sick after eating, etc.) I don't think this is unrealistic either. I, personally, would be even more afraid of what the cholinomimetic component of the drug would do to me (perhaps the only thing I fear more than food-related problems are severe episodes of sleep paralysis, cataplexy, etc., which such drugs have been known to produce), but the fear of a hypertensive crisis, even if it can be easily managed, is still going to give physicians and anxious patients pause.

I posted this a long time ago, but this MAO-B inhibitor is intriguing:

ABSTRACT

Caffeine and more specific antagonists of the adenosine A2A receptor recently have been found to be neuroprotective in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease. Here we show that 8-(3-chlorostyryl)caffeine (CSC), a specific A2A antagonist closely related to caffeine, also attenuates MPTP-induced neurotoxicity. Because the neurotoxicity of MPTP relies on its oxidative metabolism to the mitochondrial toxin MPP+, we investigated the actions of CSC on striatal MPTP metabolism in vivo. CSC elevated striatal levels of MPTP but lowered levels of the oxidative intermediate MPDP+ and of MPP+, suggesting that CSC blocks the conversion of MPTP to MPDP+ in vivo. In assessing the direct effects of CSC and A2A receptors on monoamine oxidase (MAO) activity, we found that CSC potently and specifically inhibited mouse brain mitochondrial MAO-B activity in vitro with a Ki value of 100 nM, whereas caffeine and another relatively specific A2A antagonist produced little or no inhibition. The A2A receptor independence of MAO-B inhibition by CSC was further supported by the similarity of brain MAO activities derived from A2A receptor knockout and wild-type mice and was confirmed by demonstrating potent inhibition of A2A receptor knockout-derived MAO-B by CSC. Together, these data indicate that CSC possesses dual actions of MAO-B inhibition and A2A receptor antagonism, a unique combination suggesting a new class of compounds with the potential for enhanced neuroprotective properties.>>http://www.jbc.org/cgi/content/full/277/39/36040

In reply to Re: What to do if...good thread ed » sdb, posted by ed_uk on January 2, 2006, at 14:00:15

Ed!

I have never taken another phenelzine than this from concorde pharmaceuticals. And you're 100% right about the smell; when I forgot to close the bottle the whole chamber had a strange but actually not bad perfume...

I cannot compare any forms of Nardil but form me there was a clear efficacy but you know some very unpleasant sideeffects, I think even stronger than weaker ssris (citalopram).

I am interested what company concorde pharmaceuticals is; I guess a generic supplier. It is possible that they will discontinue phenelzine(?). I have heard of other suppliers, even pfizer but the formulation seems to be more bad than the old thus less effective for some people. Maybe I am not right. I very dislike the "making money" behavior of pharmaceutical industry.